Chapter 5: Addition of the Boc-protected Amino Acid

5.1 Introduction

Various carboxylic acids have been exploited in the Ugi reaction to create different compounds such as lactams (Zhang 1999). Addition of the carboxylic acid to the imine initiates proton exchange between the imine and acid, producing the iminium ion and the carboxylate ion. This is important in the Ugi reaction, as it prepares the iminum ion for the nucleophilic addition of the isocyanide (Ugi 2003). The addition of Boc-Gly-OH to the imine formed from piperonal and 5-MFA is investigated.

5.2 Experimental

5.2.1 Materials and Reagents
Piperonal, Boc-Gly-OH, and 5-methylfurfurylamine (5-MFA) were purchased from Sigma-Aldrich Chemical Company (Milwaukee, WI). Deuterated methanol was purchased from Cambridge Isotope Laboratories, Inc. Twenty microliters (20uL) of tetramethylsilane (TMS) was added to deuterated methanol bottle to serve as an internal standard in NMR spectra. All other materials were used as received without any further modifications.

5.2.2 Synthesis (Holsey 2006)

Scheme 5.1 Reaction of Boc-Gly-OH (17) added to imine (31).

To separate one dram vials were added piperonal (16) (0.150g, 1mmol) and 5-methylfurfurylamine (18) (111uL, 1 mmol) and diluted to 1mL with deuterated methanol. NMR spectra were taken of the solutions (300 MHz) upon transfer to NMR tubes. To a five dram vial were added piperonal and 5-methylfurylamine solutions and allowed to sit for 10 minutes. The reaction was montiored via NMR for three hours. To a separate one dram vial was added Boc-Gly-OH (17) (0.175g, 1 mmol) and diluted to approximately 1mL with deuterated methanol. To the 5 dram vial was added Boc-Gly-OH solution. The reaction was monitored via NMR during periodically spaced time intervals.

5.2.3 Instrumentation Nuclear Magnetic Resonance Spectroscopy
All NMR spectra were taken on a 300 MHz Varian Inova at room temperature to determine whether the iminium ion was formed. Proton NMR spectra were taken using the standard parameters with 16 pulse signals and a 3.74 second acquisition time for CDCl3. Carbon-13 (13C) NMR spectra (CNMR) were taken with standard parameters using 50 scans and a delay of 5 seconds.

5.3 Results and Discussion
We were unable to observe the iminium ion in the NMR spectra because of poor shimming problems (Holsey 2006), however we did not see any reversion of the product back to starting materials.

This is contrary to other findings by my colleagues Khalid Mirza and James Giammarco, where addition of Boc-Gly-OH caused the imine to revert back to the aldehyde and amine (Giammarco 2007, Mirza 2007A). Further experiments were run using molecular sieves to remove water from the reaction to ensure stability of the imine, however, reversion was still observed in approximately thirty minutes. Of further interest was that the aldehyde and amine would again revert back to the imine in a matter of hours.

Further experiments (Giammarco 2007, Mirza 2007B) were conducted to see if the Ugi product would form without the addition of the Boc-Gly-OH. It was determined that the isocyanide would not react without the presence of the iminium ion, indicating that the Boc-Gly-OH is a necessary activator for the addition of the isocyanide (Ugi 2000).

5.4 Conclusion
It is important to monitor the reaction as the addition of the amino acid reverses the imine formation in approximately thirty minutes. This is important because this may hinder the Ugi product from forming in the final step after addition of the isocyanide. It would be beneficial to confirm the formation of the iminium ion before adding the isocyanide component of the reaction.

5.5 Reference List

Giammarco, J. 2007

Holsey, A. 2006

Mirza, K. 2007A
Mirza, K. 2007B

Ugi, I. and Domling, A. Multicomponent reactions of Isocyanides. Angew. Chem. Int. Ed., 39, 3168, 2000

Zhang, J.; Jacobson, A.; Rusche, J. R.; Herlihy, W. Unique Structures Generated by Ugi 3CC Reactions Using Bifunctional Starting Materials Containing Aldehyde and Carboxylic Acid". Journal of Organic Chemistry 64, 1074 1999
DOI: 10.1021/jo982192a S0022-3263(98)02192-6

Wikipedia 2007